Schizophrenia is a type of disease characterized in severely schizophrenic cognition and emotion, presenting as the influence on the basic behavior of a human, such as language, thinking, feeling, self-perception or the like. This disease encompasses a large variety of disorders, such as those involved in psyche, e.g. delusion, paranoia, illusion or the like. About 1% of the people all over the world suffer from schizophrenia, and only 5% of them can be cured after treatments. Typical anti-psychosis drug (e.g. chlorpromazine, haloperidol) blocks the dopamine D2 receptor, and severe blocking of dopamine receptor leads to extrapyramidal system (EPS) side effects, including tardive dyskinesia and increased prolactin secretion. In addition, the typical anti-schizophrenia drug is not effective for negative symptoms.
Unlike the typical anti-psychosis drug, the “non-typical” anti-psychosis drug, such as clozapine and risperidone, has low possibility of extrapyramidal system (EPS) side effects and tardive dyskinesia side effects etc. Moreover, it can effectively improve negative symptoms and cognitive disorders. However, these drugs have the side effects of extended QT interval, hyperprolactinemia, weight gain or the like. Therefore, it is important to find new anti-psychosis drug, which is effective for schizophrenia and has fewer side effect.
Through the analysis of the drugs in the market and the compounds under development, it has been found that five receptors are important for schizophrenia, i.e. D2, D3, 5-HT1A, 5-HT2A and 5-HT2C. The distribution of D3 receptor in brain mainly locates specifically at limbic system, and this system is closely related with human psychic activity. The gene variation frequency of D3 receptor in a patient with schizophrenia is significantly higher than that in control population, which is also closely related with the response to drug therapy. There are two major DA neural pathways for D3 receptor in brain: one is nigrostriatal pathway regulating the motion function, while the other is mesencephalic ventral tegmental area-accumbens nucleus-prefrontal cortex DA pathway closely associated with learning cognition and emotion behavior, of which the disorder will lead to schizophrenia. This DA pathway is the main pathway of reward effect in brain. D3 receptor is distributed in both of the DA neural pathways, and has complex interactions with other DA receptor subtypes, and thus may be the target of anti-psychosis drug therapy. Selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia, which additionally can prevent extrapyramidal system side effects, including tardive dyskinesia, Parkinson's disease or the like.
5-hydroxy tryptamine system plays an important role in modulating the function of prefrontal cortex (PFC), including emotion control, cognitive behavior and working memory. The pyramidal neurons and GABA interneurons of PFC contain several 5-hydroxy tryptamine receptor subtypes 5-HT1A and 5-HT2A in high density. It has been shown recently that PFC and NMDA receptor channels are the targets of 5-HT1A receptor, and these two receptors modulate the excitatory neuron of cerebral cortex, thereby affecting the cognitive function. In fact, various preclinical data have shown that 5-HT1A receptor may be the new target of the development of anti-psychosis drug. The 5-HT1A receptor affinity has contributed to non-typical anti-psychosis drug (e.g. olanzapine, aripiprazole or the like) and its low EPS side effects in clinical efficacy. It has been shown recently that 5-HT1A agonist is associated with non-typical anti-psychosis drug therapy, which can improve negative symptoms and cognitive disorders. In the treatment of schizophrenia with the non-typical anti-psychosis drug clozapine, it was found that 5-HT2A plays an important role in various aspects, including cognition, emotion regulation and motion control. The blocking of 5-HT2A receptor can normalize the release of dopamine, exerting the effect of anti-psychosis. In addition, 5-HT2C receptor is closely related with weight gain.
Therefore, it is needed to find novel drugs, which can extend the anti-schizophrenia scope in the manner of multiple receptor binding and has less side effects.